Global Microbial Threats in the 1990s

I. Introduction

By the mid-1950s, the threat of infectious diseases appeared to be
receding in the United States. Deaths from infection, commonplace inour
grandparents' time, were no longer a frequent occurrence.American physicians
used fast-acting, effective drugs to combatoften fatal bacterial diseases such
as meningitis and pneumonia.The incidence of childhood diseases such as polio,
whoopingcough, and diphtheria, was declining due to the use of
vaccines.Meanwhile, in other parts of the world, chemical pesticides likeDDT
were lowering the incidence of malaria, a major killer ofchildren, by
controlling populations of parasite-carryingmosquitoes.

As it turned out, our collective -- and quite understandable-- euphoria
did not take into account the extraordinary resilienceof microbes, which have a
remarkable ability to evolve, adapt,and develop resistance to drugs in an
unpredictable and dynamicfashion. Moreover, disease-carrying insects have
developedresistance to pesticides in a very short time.

Today, most health professionals agree that new microbial threatsare
appearing in significant numbers, while well-known illnessesthought to be under
control are re-emerging. Most Americans areaware of the epidemic of the
acquired immunodeficiency syndrome(AIDS) and the related increase in
tuberculosis (TB) cases in theUnited States. In fact, there has been a general
resurgence ofinfectious diseases throughout the world, including
significantoutbreaks of cholera, malaria, yellow fever, dengue, anddiphtheria,
as well as illnesses caused by antibiotic-resistantbacteria. There has also
been a resurgence of fungal infectionsfor which there are very few treatments.
Furthermore, theincidence of AIDS is increasing in many countries.

New diseases have also appeared within the United States,including Lyme
disease, Legionnaires' disease, and most recently,hantavirus pulmonary syndrome
(HPS). HPS was first recognized inthe southwestern United States in 1993 and
has since beendetected in more than 20 states and in several other countries
inthe Americas. Other new or re-emerging threats in the UnitedStates include
multi-drug resistant TB, antibiotic-resistantstaphylococcal, enterococcal, and
pneumococcal infections, anddiarrheal diseases caused by the parasite
Cryptosporidium parvumand by certain strains of Escherichia coli
bacteria. In fact,only one antibiotic remains consistently effective against
commonhospital-acquired staphylococcal infections. Meanwhile, thenumber of new
antibiotics introduced into the U.S. market hasdeclined; not one new antibiotic
was approved in 1994. In therace between drug-resistant bacteria and new drugs,
the resilientbacteria are winning.

Savings Due to Vaccination

Smallpox. The economic benefits of the Smallpox Eradication
Program have been substantial for all of the countries in the world, as
preventive measures and treatment facilities for smallpox are no longer needed.
The cost to the United States for the successful 13-year campaign to eradicate
smallpox throughout the world was about $30 million. Since smallpox was
eradicated in 1977, the total investment has been returned to the United States
every 26 days.

Polio. Once a common cause of disabilities or death, polio has
been eliminated from the Americas. The current drive towards global eradication
is one of the great challenges of our generation. Once the global eradication
program is completed (target date: 2000), the United States will save millions
of dollars yearly on vaccination costs alone, since there will no longer be a
need to immunize newborns. Based on the current rate of progress toward
eradication, WHO predicts a global savings of $500 million by the year 2000,
increasing to savings of $3 billion annually by the year 2015.

Other Infectious Diseases of Childhood. Health economists
estimate that for every dollar spent on the measles/mumps/rubella vaccine, $21
are saved; for the diphtheria/tetanus/pertussis vaccine, $29 are saved; and for
the polio vaccine $6 are saved.

Why are infectious diseases re-emerging as major threats to
humanhealth?

The reasons for the resurgence of infectious diseases are complexand not
fully understood. Contributing factors include populationshifts, increased
urbanization and crowding, environmentalchanges, and worldwide commerce and
travel. Some specific causesare

Increased human intrusion into tropical forests (for
mining,farming, settlement, and tourism), where people are most likelyto come
in contact with infected animals carrying microbes thatcause diseases in
humans. For instance, many scientists believethat the human immunodeficiency
virus (HIV), which causes AIDS,is a zoonotic pathogen which was transmitted to
humans fromnon-human primates.

Changes in human behaviors which increase the risk
ofinfection.

Population growth and changes in demographics. By
someestimates, more than 50% of the population of the world is under15 years of
age, and the proportion is increasing. This meansthat there are an enormous
number of susceptible people living inpoor and crowded urban areas, where
infectious diseases thrive.

Population shifts within and between countries, due tochanging
economic conditions or military conflicts.

Inadequacy and deterioration of public healthinfrastructures
worldwide, including a lack of communicabledisease surveillance and control
efforts for food and water-bornediseases and vaccine-preventable diseases.

Erosion of expertise on diseases such as plague,
rabies,malaria, yellow fever, and botulism.

Misuse of antibiotics or other antimicrobial drugs, whichcan
hasten the evolution of resistant microbes. This includesprescribing a drug
without proper indications, prescribing thewrong drug or the wrong dose, or
having poor patient compliancewith treatment regimens.

Ecological changes due to irrigation projects ordeforestation.
For instance, formerly dry areas may becomeexcellent habitats for
parasite-carrying insects as well as forsnails and other animals that serve as
parasite hosts.

Without preventive public health measures in the United Statesand
abroad, uncontrolled outbreaks can grow into major epidemics.However, our
earlier successes in controlling infections havebred complacency, and the
components of the U.S. public healthsystem that protects the public from
infectious microbes havebeen neglected, concentrating their resources on a few
targeteddiseases.

Nevertheless, the subject of emerging infectious diseases isbeginning to
receive sustained public attention. In 1992, theInstitute of Medicine's report,
"Emerging Infections: MicrobialThreats to Health in the United States,"
clarified the issue ofemerging diseases for policymakers in government and in
academia.In response, the CDC issued the 1994 report "Addressing
EmergingInfectious Disease Threats: A Prevention Strategy for the
UnitedStates." Other U.S. Government agencies, including NIH, USAID,and DoD
have also examined the issue of U.S. vulnerability toepidemics and re-emerging
health problems.

Quite recently, public discussion has been further focused on theglobal
issue of emerging diseases by the publication of twobest-selling, non-fiction
books, The Hot Zone by Richard Preston,and The Coming Plague by
Laurie Garrett, and by popular moviessuch as "Outbreak," starring Dustin
Hoffman. Concerns aboutantibiotic-resistant bacteria and food-borne diseases,
as well asthe recent plague outbreak in India and the Ebola outbreak inZaire,
have been widely discussed in many news magazines, inprint and on television.
This media attention has informed theAmerican public of the reasons why it is
in our national interestto strengthen disease surveillance and control
effortsinternationally.

International health and U.S. foreign policy

A global system for infectious disease surveillance and responsewill
help protect the health of American citizens and peoplethroughout the world. In
addition, the improvement ofinternational health is a valuable component of the
U.S. effortto promote worldwide political stability through sustainableeconomic
development. Healthy people are more productive andbetter able to contribute to
their countries' welfare. Also, aglobal disease surveillance and response
network will enable theUnited States to respond quickly and effectively in the
event ofan attack involving biological or chemical warfare, as theexperience
gained in controlling naturally occurring microbeswill enhance our ability to
cope with a biological warfare agent,should the need arise. The release of
nerve gas in the Tokyosubway system in March 1995 has underscored our need to
be wellprepared to counteract deliberate attempts to undermine humanhealth.

Thus, the effort to build a global surveillance and responsesystem is in
accord with the national security and foreign policygoals of the United States.
Moreover, leadership in globalinfectious disease surveillance and control is a
natural role forthe United States. American business leaders and scientists
arein the forefront of the computer communications and biomedicalresearch
communities (both public and private sector) thatprovide the technical and
scientific underpinning for diseasesurveillance. Furthermore, American
scientists and public healthprofessionals have been among the most important
contributors tothe international efforts to eradicate smallpox and polio.

The challenge ahead outstrips the means available to any onecountry or
to international organizations. The U.S. Governmentmust not only improve its
capacity to meet the growing threat ofemerging infectious diseases, but also
work in concert with othernations and international bodies. Although
international effortsmust be coordinated to prevent global pandemics,
diseasesurveillance must be the responsibility of each sovereign
nation.However, individual governments may not easily share nationaldisease
surveillance information, fearing losses in trade,tourism, and national
prestige. Nevertheless, because U.S.experts are often consulted on problems of
infectious diseaserecognition and control, the U.S. Government is usually
informedabout major disease outbreaks in other countries, although notalways in
an official or timely fashion. To ensure that wecontinue to be notified when an
unusual outbreak occurs, we mustencourage and support other countries' efforts
in nationaldisease surveillance and respond when asked for assistance. Wemust
strive to develop a sense of shared responsibility andmutual confidence in the
international effort to combatinfectious diseases.

There is much room for optimism. If the United States takes thelead, we
can expect that other nations will contribute resourcesto a global surveillance
system. Both Canada and the EuropeanUnion have recently decided -- in spite of
tight budgets -- toprovide substantial funds ($7 and $10 million per
year,respectively) to strengthen infectious disease surveillance andcontrol. It
is also absolutely critical that developing nationsbe engaged in an
international effort that is in their owninterests. In May 1995, WHO passed a
resolution urging memberstates "to strengthen national and local programmes
ofsurveillance for infectious diseases, ensuring that outbreaks ofnew,
emerging, and re-emerging infectious diseases areidentified." Soon after the
resolution was drafted, WHO issued areport urging the strengthening of global
disease surveillanceand control, and encouraging greater use of WHO
CollaboratingCenters in this endeavor.

Are infectious disease surveillance and control cost-effective?

The direct and indirect costs of infectious disease arestaggering (see
Table 1). Clearly, public health measures thatprevent
infectious diseases can be extremely cost-effective. In 1994 and 1995 two major
U.S. health-care expenses have beenfor the treatment of tuberculosis and AIDS.
The Public HealthService budget for fiscal year 1996 includes $343 million
tocombat TB and nearly $3 billion to combat AIDS. TB is a very old,well-known
disease that has re-emerged sometimes in adrug-resistant or multidrug-resistant
form. AIDS, on the otherhand, is a new disease, unrecognized before the 1980s.
When thefirst cases of AIDS and drug-resistant TB were detected in theUnited
States, control measures were delayed, partly because of alack of surveillance
information and incomplete understanding ofthe epidemiology of these
diseases.

These costs, combined with dollars spent on AIDS and TB, exceed $120
billion per year.

Tuberculosis

For many years, the United States had in place a surveillancesystem to
monitor cases of TB. However, during the 1980s, federaland local spending on
infectious disease control declined, and in1986 the surveillance system for
multidrug-resistant TB wasdiscontinued. Consequently, there was no warning
signal whendrug-resistant TB emerged in the late 1980s. This lack of
earlywarning undoubtedly contributed to the more than $700 million indirect
costs for TB treatment incurred in 1991 alone.Surveillance of drug-resistant TB
was not reinstated until 1993,by which time multidrug-resistant TB had became a
public healthcrisis and millions of federal dollars had been appropriated.

AIDS

As mentioned above, AIDS is a new disease that was unknown beforethe
1980s, and thus, was not on any surveillance lists. AIDSweakens the immune
system, allowing other infections to takehold. Therefore, it can be difficult
to diagnose since itsclinical presentation may involve a variety of symptoms,
and itsincubation period (the time between infection and the appearanceof
symptoms) can be many years. Nevertheless, long before AIDSwas diagnosed in the
United States and Europe, a distinctsyndrome called slim disease (now known to
be a form of AIDS)that causes its victims to waste away was recognized by
Africandoctors. In fact, an aggressive, slim-associated, generalizedform of
Kaposi sarcoma, distinct from the classical form, hasbeen described in Uganda
since at least 1962. Some health workersbelieve that if a global surveillance
network had been in placein the 1970s, AIDS might have been identified earlier,
perhapsbefore it became well established in the United States.Epidemiologists
might have gained a head start in learning howAIDS is transmitted and
prevented, and many lives might have beensaved. However, other health experts
believe that the lack ofdisease surveillance and specimen collection facilities
incentral Africa in the 1960s and 1970s make it nearly impossibleto be sure,
even in retrospect, if AIDS was present at that time.

Human demographics; microbial adaptation; international travel and
commerce; misuse and overuse of antibiotics

Cholera

Travel: a new strain (O139) apparently introduced to South America
from Asia by ship, with spread facilitated by reduced water chlorination and
also food

Common Types of Antimicrobial Drug Resistance

In recent years, antimicrobial drug resistance has become aserious
problem in the United States and abroad. Antimicrobialresistance occurs when a
disease-carrying microbe (bacteria,virus, parasite, or fungus) is no longer
affected by a drug thatpreviously was able to kill the microbe or prevent it
fromgrowing.

The types of antimicrobial drug resistance include

Antibiotic resistance. Resistance to drugs that kill bacteria
orkeep them from growing. Antibiotic resistance is a growingproblem in American
hospitals. It affects the treatment ofbacterial pneumonia, TB, ear infections,
and many other commonbacterial illnesses.

Antiviral resistance. Resistance to drugs that prevent
thereplication of viruses. Antiviral resistance is a serious problemin the
treatment of AIDS, which is caused by the HIV retrovirus.For instance, most
strains of HIV become resistant over time tothe drug AZT, which is a first-line
drug against AIDS.

Antiparasite resistance. Resistance to drugs that kill
parasitesor keep them from growing. For example, common medicines
andprophylactic treatments for malaria, including chloroquine, areno longer
reliably effective because drug resistance is spreadingamong malarial
parasites.

Antifungal resistance. Resistance to drugs that kill fungi orkeep
them from growing. Drug resistance has developed to thedrugs for the treatment
of candida infections which are common inAIDS patients worldwide.

Multidrug resistance. A bacterium, parasite, or fungus which
hasdeveloped resistance to several previously potent drugs,sometimes through a
non-specific mechanism that allows themicrobe to eject or neutralize drugs of
different chemicalstructures. In the United States, multidrug-resistant TB is
onthe rise.

Pesticide resistance. A microbe-carrying insect or animal(disease
vector) becomes resistant to an agent that previouslywas used to kill it. The
most common type of pesticide resistanceis insecticide resistance. Insecticides
are used in many parts ofthe world to kill mosquitoes that carry malaria
parasites. Otherinsect vectors include tsetse flies (which carry parasites
thatcause African sleeping sickness) and reduviid bugs (which carryparasites
that cause Chagas' disease, a serious disease prevalentin South America.)

Lessons Learned From the Ebola Virus Outbreak in
Zaire

(Written on May 18, 1995, one week after the CDC team arrived
inKikwit, Zaire)

Researchers at CDC's biosafety level-four laboratory in Atlanta,Georgia,
confirmed on May 10 that a mysterious disease outbreakin Kikwit, Zaire, was
caused by the deadly Ebola virus. On thefollowing day, the Government of Zaire
informed its citizens ofthe danger and began to institute quarantine measures.
At thegovernment's invitation, WHO investigators arrived in the capitalcity,
Kinshasa, on May 10, where a 3-person CDC team joined themon May 11.

A few days earlier, on May 6, the U.S. Embassy in Zaire hadlearned that
Kikwit, an area about 350 miles from Kinshasa, wassuffering an outbreak of an
unusual hemorrhagic fever.

A medical professor at the University of Kinshasa reported thatthe
symptoms of the fever patients were the same as those seen inan earlier Ebola
outbreak (in 1976). The Ebola virus, which istransmitted through contact with
infected bodily fluids, causes afatal illness in 50-90 percent of its victims,
and there is noknown drug treatment or vaccine.

The Government of Zaire has quarantined the Kikwit area andclosed the
road leading from Kinshasa to Bandundu State, whereKikwit is located. The U.S.
Embassy has declared the outbreak adisaster, and USAID's Office of Foreign
Disaster Assistance(OFDA) has authorized the payment of $25,000 to
non-governmentalorganizations (NGOs) in the area for the purchase and
transportof disposable protective clothing, plasma, body bags, andessential
medicines and supplies. OFDA has also requested aDepartment of Defense airlift
to transport equipment andsupplies, including plasma, plastic hospital gowns
and sterileneedles.

The Vice Prime Minister of Zaire, Kamanda Va Kamanda, accompaniedthe WHO
and CDC doctors to Kikwit on May 12, where theinternational team set about its
primary task of containing theoutbreak of Ebola fever. As part of that effort
the team istrying to trace the outbreak's first casualty to gain clues tothe
virus's animal or insect host (its "reservoir"). Theinternational team has been
joined by additional doctors fromZaire and elsewhere, including government and
NGO medical workersfrom Belgium, South Africa, and Sweden.

The different national groups that make up the WHO-ledinternational team
bring different resources and types ofexpertise to the cooperative effort. For
instance, Belgiandoctors from the organization Medicins Sans Frontieres focus
onproviding clinical care and specialize in building and operatingsafe,
sanitary, functional hospitals and clinics. Zairian doctorsfrom the University
of Kinshasa are familiar with most localhealth problems and take the lead in
clinical diagnosis, casemanagement, and clinical work-up. The CDC team provides
expertisein filoviruses (the class of virus to which Ebola belongs),experience
in disease surveillance and case investigation, andaccess to laboratory
diagnosis via the facilities in Atlanta.

Lessons from Kikwit. It is useful to examine the
internationalteam's experiences in Zaire for ideas on how to improve
U.S.preparedness for controlling infectious diseases outbreaks incountries with
poorly developed health and communicationsinfrastructures. One week into the
investigation, the three CDCinvestigators report that the team's efforts are
hampered bydifficulties with transportation and communication, and by lackof
money and personnel. Because the average incubation time (thetime between
infection and the appearance of symptoms) for Ebolais 7 days, each week's delay
in instituting control measuresmeans that a new generation of the virus has
time to spread.

1) Transportation. To investigate suspected Ebola cases,
doctorsmust be able to travel quickly from community to community in anarea
where there are few paved roads and no publictransportation. The USAID mission
to Zaire, which in past yearscould be relied on for assistance with logistics
andorganization, was closed in 1994. The U.S. Embassy and OFDA haveprovided
some help, as the CDC team did not arrive in Zaire withauthorization to
purchase or rent cars or bicycles.

2) Money. The CDC team in Kikwit has no funds at their disposalto
obtain radios, cars, bicycles, or additional medical supplies.An initial
$20,000 was spent on essential equipment and medicalsupplies. A week into the
investigation, the team has requested$781,000 to allow six doctors to work in
Zaire for three months.In comparison, the team that responded to the hantavirus
outbreakin New Mexico in 1994 involved 24 people working for 18 months ata cost
of 4.5 million dollars. (Note: On May 23 OFDA allocated$750,000 for the CDC
team and USAID's Bureau of Global ProgramsField Support and Research supplied
another $43,000.)

3) Personnel. The Zairian medical authorities have requested
thatthe CDC send three additional epidemiologists and oneoperations/logistics
manager to provide help with travel,communications, and procurement. In the
United States, at CDC'sbiosafety level-four laboratory in Atlanta,
additionaltechnicians are needed to process the hundreds of
potentiallydangerous clinical samples sent from Zaire. The internationalteam
(not only the CDC doctors) are dependent upon the efforts ofthis unique
laboratory. (Update: The funds provided by USAID/OFDAon May 23 will be used to
support additional personnel in Zaire.)

4) Communication. To prevent the spread of Ebola fever,
medicalworkers must report all suspicious fever cases to the nationalhealth
authorities so that appropriate follow-up measures can beinstituted. There are
very few telephones and no radio station inKikwit, although radio transmissions
are received from Kinshasa.The lack of reliable communication has hampered the
internationalteam members' initial efforts to coordinate with each other andthe
national health authorities of Zaire.Poor communication has been a problem
from the beginning of theoutbreak. Although the first case of Ebola probably
occurred asearly as December, 1994, the international community only
learnedabout the outbreak in May, after the Ebola virus had nearly 20weeks to
spread. This delay reflects the weak health care systemsand the poor state of
infectious diseases surveillance in most ofAfrica. Over the last ten years,
with the end of thepost-colonial era, the end of the Cold War, and the decline
ofWestern interest in tropical medicine, the public healthinfrastructures in
many African countries have deteriorated.Infectious disease surveillance is
nearly non-existent, andemerging and re-emerging diseases frequently go
unreported.